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J M Hoffman

Publications and source records attributed to J M Hoffman.

154 records · Page 9Linked to original sources
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Binding of the hypoxia tracer [3H]misonidazole in cerebral ischemia.

Radiolabelled misonidazole, a radiosensitizing drug that binds to viable hypoxic tumor cells, may be useful in identifying hypoxic cells in cerebrovascular disease. Its potential was investigated in the gerbil stroke model. Biodistribution of [3H]misonidazole was measured in normal gerbils and animals that had been subjected to right common carotid artery ligation to produce cerebral ischemia. The uptake of [3H]misonidazole in the right cerebral hemisphere and right/left hemispheral uptake ratios correlated positively with the severity of the stroke when measured 6-9 hours after carotid ligation. Histologic studies in symptomatic ligated animals showed ipsilateral widespread but patchy acute ischemic changes as well as areas that showed no morphological changes. Microscopic autoradiography in these animals showed diffuse heavy labelling only in the ipsilateral hemisphere. This was over areas that had histological damage as well as in adjacent areas that appeared intact. Studies comparing blood flow measured with [14C]iodoantipyrine and [3H]misonidazole retention in gerbils with carotid artery ligations indicated that flow is not a major determinant of retention of this hypoxia tracer. We conclude that a misonidazole congener labelled with a gamma- or positron-emitting isotope may be useful in nuclear imaging of the degree and regional distribution of hypoxic tissue in cerebrovascular disease.

Animals↗
PubMedDate not supplied

Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-Dopa uptake and metabolism after intracerebral implantation in nonhuman primates.

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 10(8) fmol/min x 10(6) cells, and that this uptake can be specifically blocked 88% by the addition of 10nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP-treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18-F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5-13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer-encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Differentiation of central nervous system lesions in AIDS patients using positron emission tomography (PET).

To determine if positron emission tomography (PET) imaging using F-18 fluorodeoxyglucose (FDG) can accurately distinguish between malignant and infectious central nervous system (CNS) mass lesions in patients with human immunodeficiency virus (HIV) infection, a prospective case series of 18 patients with HIV infection and focal CNS lesions on computed tomography (CT) or magnetic resonance (MR) scans was analysed. The patients were divided into 3 groups based on biopsy results, serology and response to therapy. Group 1 consisted of 8 patients with infectious lesions (4 with toxoplasmosis, 2 with neurosyphilis, 2 with progressive multifocal leukoencephalopathy (PML)). Group 2 consisted of 5 patients with biopsy proven CNS lymphoma. Group 3 consisted of 5 patients with presumed CNS lymphoma. Patients underwent FDG-PET studies as an adjunctive diagnostic procedure. The metabolic activity of each patient's lesion was graded using both a qualitative visual score and a semi-quantitative count ratio comparing the lesion with contralateral brain. CNS lesions diagnosed as lymphomas had statistically higher visual scores (P = 0.001) and count ratios (P = 0.002) than CNS lesions diagnosed as infections. FDG-PET could accurately differentiate lymphoma from infections in 16 of 18 cases. Two cases of PML had high metabolic activity and could not be differentiated from lymphoma. FDG-PET shows great promise in differentiating lymphoma from infectious lesions in the CNS of patients with HIV infection. If larger prospective studies confirm this impression, more specific and rapid treatment of CNS lesions could be performed and perhaps obviate the need for brain biopsy in many cases.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices.

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.

Animals↗
PubMedDate not supplied

Modern concepts in crown preparation.

The preparation of teeth for full coverage is one of the most abused procedures in fixed prostheses. It is fallacious to discard precision preparations on the grounds that they will not be visible once the crown is constructed. In truth, what takes place in the preparation phase of crown and bridge construction determines the quality of the final restoration.

Crowns↗
PubMedDate not supplied

Metabolism of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2 (1H)-one (L-696,229), an HIV-1 reverse transcriptase inhibitor, by rat liver slices and in humans.

Healthy subjects were administered single oral doses of 800 mg or 400 mg 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne (L-696,229), a nonnucleoside inhibitor of the human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT). Plasma or urine samples were collected over a period of 48 hr. Pooled plasma (0.5-6 hr) and urine (0-24 hr) samples were analyzed by HPLC-UV and HIV-1 RT inhibition assay using poly rC.dG as a template primer. The parent compound and several common metabolites were detected in both samples. The metabolic profiles were also similar to those obtained from a rat liver slice incubation with [3H]L-696,229. The in vitro metabolites were identified by NMR and MS as 5 alpha-hydroxyethyl- (major), 5,6-dihydrodiol-, 6'-hydroxy-, 6-hydroxymethyl-, and 5-vinyl analogs, and a benzoxazole ring hydrolysis product. Most of the significant metabolites in human plasma and urine were found to be identical to the in vitro metabolites, as established by HPLC-UV and MS. Hydrolysis of the plasma and urine with beta-glucuronidase/sulfatase indicated the presence of significant amounts of conjugates of the parent compound and 5 alpha-hydroxyethyl metabolite. Most of the other primary metabolites were also present in conjugated forms, albeit in small quantities. In addition, two secondary metabolites were isolated and identified from the hydrolyzed urine as 5-acetyl-6'-hydroxy- and 5 alpha-hydroxyethyl-6-hydroxymethyl- analogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

[18F]2-fluoro-2-deoxyglucose-positron emission tomography correlation of gadolinium-enhanced MR imaging of central nervous system neoplasia.

PURPOSE: To correlate the findings of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced MR imaging with positron emission tomography (PET) in the evaluation of central nervous system neoplasia. MATERIALS AND METHODS: Thirty-six lesions identified on noncontrast MR in 35 patients with biopsy-proved intracranial tumors were imaged with both T1-weighted Gd-DTPA MR at 1.5 T and [18F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET). Eighteen women and 17 men with a mean age of 47.1 years (range 22-72) were studied. The degrees of Gd-DTPA enhancement and FDG uptake were rated separately, and then all scans were reviewed together. FDG uptake was graded 1-5. RESULTS: Of the 35 lesions rated, 30 had Gd-DTPA enhancement and 28 of these were hypermetabolic (FDG accumulation greater than white matter) on PET (93% concordance). Twenty-six of 32 neoplastic lesions had Gd-DTPA enhancement. Twenty-four of these enhancing tumors were hypermetabolic. Only one lesion was completely missed on PET but identified on routine spin echo MR. CONCLUSION: Gd-DTPA MR and FDG-PET are complementary and there is a high concordance of Gd-DTPA-enhancing tumours displaying FDG hypermetabolism. Although FDG hypermetabolism and Gd-DTPA enhancement are usually suggestive of high-grade malignancy, anaplastic astrocytomas may not enhance with Gd-DTPA and can be hypometabolic. In addition, benign intracranial tumors (two cases of meningioma) and radiation necrosis can be associated with both FDG uptake and Gd-DTPA enhancement.

Adult↗